Is the Brain Ready for Personalized Medicine? Studies Suggest Not Quite Yet.

Jason Karlawish, MD, is a professor of medicine, medical ethics and health policy at the University of Pennsylvania and the director of Penn’s Neurodegenerative Disease Ethics and Policy Program. He is the recipient of a Robert Wood Johnson Foundation Investigator Award in Health Policy Research.

“Prescribe the right drug to the right patient at the right time” is not a new medical practice, but when a biomarker—that is, a measure of disease pathophysiology—or a gene makes this decision, that is a radically new medical practice. The promise of personalized medicine is that biomarker and gene driven algorithms will do much of the work of medicine. By predicting patients’ future health and the outcomes of an intervention, they will guide what doctors recommend to their patients. Like the theory of evidence-based medicine, personalized medicine promises a more objective, efficient and precise medical practice.

To date, personalized medicine has largely flourished “below the neck,” that is, in the care of patients with common medical diseases, particularly cancer and cardiovascular disease. In the last two decades though, the National Institutes of Health, the pharmaceutical industry, and researchers have invested substantial time and money in research such as the Alzheimer’s Disease Neuroimaging Initiative (called “ADNI”) dedicated to discovering and validating the biomarkers and genes that predict whether a brain will fail. This research is beginning to reshape how we talk about the diagnosis and treatment of the aging brain, an organ that is more and more, like hearts and bones, regarded as an organ “at risk.” As a result, clinicians, ethicists, and health care policy-makers are beginning to ask how we should practice personalized medicine for the seemingly healthy brain that is at risk for neurodegenerative dementias such as Alzheimer’s, Parkinson’s, Lewy Body Disease and frontotemporal lobar degeneration.

This July, at the Alzheimer’s Association’s International Conference in Boston, my colleagues Leo Waterston, Robert Green and I presented research to answer this question. We reported what happens to a person when she learns a personalized estimate of her lifetime genetic risk of developing Alzheimer’s disease dementia.

In a 2009 New England Journal of Medicine paper, Dr. Green’s REVEAL study showed that after a person learns she is a carrier of a gene variant that increases one’s risk of developing Alzheimer’s dementia, called the APOE e4 variant, she doesn’t experience sustained psychological harms. In the study we presented in Boston, we took these analyses one step further. We examined the subgroup of persons who are APOE4 positive and who have not one, but two copies of the e4 allele. This is a small cohort—just 4 percent of the general population—but estimates are that such persons have a lifetime risk of developing Alzheimer’s disease dementia that is as high as 90 percent.

Compared to persons who only have one or no copies of the APOE e4 variant, what happens when you learn you have two copies of this gene, that is, you are “an APOE e4 homozygote?”

The APOE e4 homozygotes were no more likely than persons who carried no copies of the APOE e4 variant to experience clinically significant depression or anxiety. But they did differ in other respects. They were more likely than persons with just one copy of the e4 variant to engage in behaviors that might reduce their risk, such as changes in diet or exercise.

Right now, motivated individuals can purchase the results of their APOE genetic profile from a commercial vendor such as 23andMe. The pressing clinical and public policy question is whether APOE assessments of the risk of brain failure are ready for clinical practice. In short should doctors prescribe, and health care systems reimburse, genetic testing for the risk of Alzheimer’s disease? And what about biomarker assessments of neurodegeneration? Last year, the FDA approved PET amyloid imaging as a test to assess whether a person with cognitive complaints does or does not have one of the pathologic signatures of Alzheimer’s disease dementia. The number of people who might seek such testing could be in the millions.

The simple answer to the question “Is personalized medicine is ready for the brain?” is no, not yet, especially in the case of costly tests such as PET amyloid imaging. Why? The Centers for Medicare & Medicaid Service’s controversial decision to decline coverage for PET amyloid imaging shows that the Ground Zero of debate is all about demonstrating value. What is the value of learning your brain is at risk of failing?

Answers to this question need to show that gene or biomarker “positive” people do things that improve their health and reduce the costs of health care. The REVEAL Study suggests that some do. The discovery of a medication that would slow cognitive decline in persons who are at heightened genetic or biomarker risk would be of tremendous value, assuming the medication is priced affordable to its value. Presently, there are at least three clinical trials enrolling cognitively normal subjects who have genetic or biomarker positive profiles. These prevention trials are a bold attempt to prove whether we can slow the creep of cognitive decline that ultimately disables many older adults.

Value, though, is not simply a tally of a drug intervention’s benefits. It has a flip side: harm. Genes such as APOE are relatively static measures present since birth and therefore perhaps one of the reasons learning one is a double APOE e4 carrier is not harmful. Biomarkers, though, are far more dynamic measures of a failing brain. The shrinkage of the hippocampi seen on MRI imaging or the accumulation of amyloid on PET imaging are the signatures of a failing brain.

This month, in Neurology, my group published the results of a survey of ADNI investigators’ views on returning amyloid imaging results to subjects in ADNI. At present, although about half of the cognitively normal subjects are asking to learn their amyloid scan results, few, if any, researchers are telling subjects these results. However, half of those investigators reported that they would like to tell them, but they carefully qualified their willingness. The investigators want evidence-based guidance on how to tell a person his result, and studies of how people react to learning biomarker-based information about their brain being at risk.

We need to prove that people who want to learn this information can live with it and that they will adopt “brain healthy” behaviors. We also need to prove that telling a person her amyloid scan suggests her brain is at risk for decline does not begin to engender a belief that accelerates that decline. Last year’s Alzheimer’s meeting in Vancouver, Canada presented a provocative study from David Solomon and colleagues at the University of California at San Diego. They found that people who learn they are APOE e4 positive perform worse on cognitive tests compared to people who are APOE e4 positive but do not know this information.

This disturbing result evokes the results of years of experimental psychology research showing that when persons who expect to do poorly on achievement tests are given an achievement test, they perform poorly, but when the same test is not called an achievement test, they perform better. Culture and belief may transform a gene or biomarker result from simple data we input into an algorithm, into a stereotyped threat.

Clinicians, researchers and companies are eager to move personalized medicine above the neck, and surveys suggest that some people are eager to learn this information and some doctors want to tell it to them, but research needs to prove that the brain is ready for personalized medicine.